Seven decades of antipsychotic drugs: Why is the life of Australians with schizophrenia still so suboptimal?

The advent of dopamine (D2) receptor-blocking medications over 70 years ago, ushered in a new era of biological treatment for schizophrenia. However, we argue that little subsequent progress has been made in translating this into fulfilled and fulfilling lives for people with schizophrenia. This Viewpoint asks why this is the case, and suggests ways forward for capitalising on extant and emerging new treatments for psychotic disorders, to the betterment of the lives of people living with schizophrenia.

Binding of SEP-363856 within TAAR1 and the 5HT1A receptor: implications for the design of novel antipsychotic drugs.

Current medications for schizophrenia typically modulate dopaminergic neurotransmission. While affecting positive symptoms, antipsychotic drugs have little clinical effect on negative symptoms and cognitive impairment. Moreover, newer 'atypical' antipsychotic drugs also have significant metabolic adverse-effects. The recent positive clinical trial of the novel drug candidate SEP-363856, which targets non-dopamine receptors (trace amine-associated receptor and the 5HT1A receptor), is a potentially promising development for the management of schizophrenia. In this perspective, we briefly overview the role of TAAR1 and the 5HT1A receptor in schizophrenia and explore the specific binding characteristics of SEP-363856 at these receptors. Molecular dynamics simulations (MDS) indicate that SEP-363856 interacts with a small, common set of conserved residues within the TAAR1 and 5HT1A ligand-binding domain. The primary interaction of SEP-363856 involves binding to the negatively charged aspartate residue (Asp1033.32, TAAR1; Asp1163.32, 5HT1A). In general, the binding of SEP-363856 within TAAR1 involves a greater number of aromatic contacts compared to 5HT1A. MDS provides important insights into the molecular basis of binding site interactions of SEP-363856 with TAAR1 and the 5HT1A receptor, which will be beneficial for understanding the pharmacological uniqueness of SEP-363856 and for the design of novel drug candidates for these newly targeted receptors in the treatment of schizophrenia and related disorders.

Association between long-term use of prolactin-elevating antipsychotics in women and the risk of breast cancer: What are the clinical implications?

BACKGROUND: Some antipsychotic drugs elevate prolactin, and hyperprolactinaemia is associated with an increased risk of breast cancer. Women with schizophrenia have an increased incidence of breast cancer, but also multiple risk factors for the condition. METHOD: This paper will critically review recent epidemiological studies concerning antipsychotics and breast cancer from a psychiatric perspective. RESULTS: Two recent epidemiological studies have found an association between use of prolactin-elevating antipsychotics and breast cancer in women with schizophrenia and other psychotic disorders. Prolactin-elevating drugs include paliperidone, risperidone, amisulpride and haloperidol, whilst prolactin-sparing antipsychotics included aripiprazole, brexpiprazole, cariprazine and quetiapine. In the two studies, estimated increased risks of breast cancer were disconcertingly high (up to 62%), but a third recent study found only a weak dose-response association. There are extensive methodological complications in this research, including the extent to which studies measure other risk factors for breast cancer and disagreement about the extent of prolactin elevation by some antipsychotics. CONCLUSION: Although causation between prolactin elevating antipsychotics and breast cancer in women has not been demonstrated, recent epidemiological reports are worrying. For women on antipsychotics, informed consent should ideally include discussion of breast cancer concerns within the wider context of treatment benefits and risks.

What clinicians need to know about intranasal esketamine for treatment-resistant depression?

OBJECTIVE: To review the usefulness of esketamine for treatment-resistant depression. METHOD: Pivotal trials of intranasal esketamine in treatment-resistant depression were synthesized as a narrative review. RESULTS: Esketamine is postulated to act through antagonism of N-methyl-D-aspartate (NMDA) glutamate receptors, but opioidergic effects may also be involved. Unlike intravenous ketamine, esketamine is given intranasally (under clinical observation), usually in addition to an oral antidepressant. Trials compared esketamine plus antidepressant versus placebo plus antidepressant. At 4 weeks, remission was 37% higher with esketamine/antidepressant than placebo/antidepressant. Speed of response and improvement in suicidality were comparable. In stable remitters on esketamine/antidepressant, 45% relapsed when esketamine was withdrawn over the following 6 months (whereas 25% relapsed on esketamine/antidepressant). Response appears less likely in patients with multiple antidepressant failures. Adverse effects include dissociation, dizziness, nausea, sedation, and headache but no psychosis. Hypertension affected 13%, especially older patients. Dose frequency is twice-weekly for 4 weeks, then weekly/fortnightly thereafter. No abuse has been reported. Unsubsidised cost may be beyond the reach of many Australians. CONCLUSION: Intranasal esketamine plus antidepressant has been approved by regulators as moderately effective and acceptably tolerable for treatment-resistant depression. Cost is a drawback. Use often needs to be long-term and vigilance for abuse is essential.

Real-world performance of Victorian hospitals during the COVID-19 lockdowns.

OBJECTIVE: Victoria has low numbers of general adult psychiatric beds per capita by Australian and international standards. Hospital key performance indicators (KPIs) such as bed occupancy rates, emergency department waiting times and inpatient lengths of stay are proximal measures of the effects any shortfall in beds. We investigate the real-world performance of Victorian hospitals during the first year of the COVID-19 pandemic and the extended lockdowns in 2020. CONCLUSIONS: The Victorian inpatient psychiatric system is characterised by high bed occupancies in many regions, extended stays in emergency departments awaiting a bed, and short inpatient lengths of stay, except for patients with excessively long stays on acute units (over 35 days) who are unable to be admitted to non-acute facilities. At the end of 2020, bed occupancies were high (above 90%) in 10 regions, with three regions having bed occupancies over 100%. However, state-wide average bed occupancy improved between 2019 (94%) and 2020 (88%). Other KPIs remained steady because acute hospitals did not experience the expected pandemic mental health demand-surge. For a more complete picture of the impact of the pandemic, Australia needs interconnected, centralised data systems.

The challenges facing the public mental health sector: implications of the Victorian Psychiatry workforce project.

OBJECTIVES: This paper reviews the major findings of the Victorian Psychiatry Attraction, Recruitment and Retention Needs Analysis Project and considers some of the implications for the psychiatrist workforce working in public sector psychiatry. CONCLUSIONS: The report provides a snapshot of the issues that are impairing the ability of Victorian psychiatrists to comprehensively treat those in our community who have severe mental illness. As the report shows, the issues impacting the profession are multi-faceted and complex, yet surmountable.

Milnacipran: serotonin-noradrenaline reuptake inhibitor approved for fibromyalgia may be a useful antidepressant.

OBJECTIVE: Milnacipran is a serotonin noradrenaline reuptake inhibitor (SNRI) approved for treatment of fibromyalgia in Australia, but is used for depression in Europe and elsewhere. This paper will briefly review milnacipran and its utility in psychiatry for the treatment of depression. CONCLUSION: Milnacipran is a dual reuptake inhibitor of noradrenaline and serotonin, with greater effect on noradrenaline than serotonin, in contrast to the related drugs venlafaxine, desvenlafaxine and duloxetine. Rapidly absorbed irrespective of food, milnacipran has a half-life of approximately 8 hours, reaches steady state in 2 days and is excreted renally. Milnacipran helps a minority of patients with fibromyalgia by reducing pain and fatigue. It is also an effective antidepressant with efficacy comparable to venlafaxine and duloxetine, and a side effect profile characteristic of SNRIs. The dose range is 50-200 mg, in divided doses. Milnacipran may be useful for patients with depression and pain, and endogenous depression characterised by anergia, psychomotor retardation and hypersomnia. Caution is necessary in the presence of heart disease, hypertension, renal impairment, epilepsy, glaucoma, bipolar disorder, and bleeding tendency. Milnacipran is likely to be a useful late antidepressant option in treatment-resistant patients, as well as those with chronic pain, anergia and hypersomnia.

Acceptance and commitment therapy for psychosis: randomised controlled trial.

BACKGROUND: The efficacy of acceptance and commitment therapy (ACT) in psychosis has been reported but not for medication-resistant psychosis. AIMS: To test the efficacy of ACT in a sample of community-residing patients with persisting psychotic symptoms. (Australian New Zealand Clinical Trials Registry: ACTRN12608000210370.) METHOD: The primary outcome was overall mental state at post-therapy (Positive and Negative Syndrome Scale - total); secondary outcomes were psychotic symptom dimensions and functioning. In total, 96 patients were randomised to ACT (n = 49) or befriending (n = 47). Symptom, functioning and process measures were administered at baseline, post-therapy and 6 months later. RESULTS: There was no group difference on overall mental state. In secondary analyses the ACT group showed greater improvement in positive symptoms and hallucination distress at follow-up: Cohen's d = 0.52 (95% CI 0.07-0.98) and 0.65 (95% CI 0.24-1.06), respectively. CONCLUSIONS: Improvements reflected the treatment focus on positive symptoms; however, absence of process-measure changes suggests that the ACT intervention used did not manipulate targeted processes beyond befriending. Symptom-specific therapy refinements, improved investigation of process and attention to cognitive functioning and dose are warranted in future research.

A randomised controlled trial of acceptance and commitment therapy (ACT) for psychosis: study protocol.

BACKGROUND: Cognitive behavior therapy for psychosis has been a prominent intervention in the psychological treatment of psychosis. It is, however, a challenging therapy to deliver and, in the context of increasingly rigorous trials, recent reviews have tempered initial enthusiasm about its effectiveness in improving clinical outcomes. Acceptance and commitment therapy shows promise as a briefer, more easily implemented therapy but has not yet been rigorously evaluated in the context of psychosis. The purpose of this trial is to evaluate whether Acceptance and Commitment Therapy could reduce the distress and disability associated with psychotic symptoms in a sample of community-residing patients with chronic medication-resistant symptoms. METHODS/DESIGN: This is a single (rater)-blind multi-centre randomised controlled trial comparing Acceptance and Commitment Therapy with an active comparison condition, Befriending. Eligible participants have current residual hallucinations or delusions with associated distress or disability which have been present continuously over the past six months despite therapeutic doses of antipsychotic medication. Following baseline assessment, participants are randomly allocated to treatment condition with blinded, post-treatment assessments conducted at the end of treatment and at 6 months follow-up. The primary outcome is overall mental state as measured using the Positive and Negative Syndrome Scale. Secondary outcomes include preoccupation, conviction, distress and disruption to life associated with symptoms as measured by the Psychotic Symptom Rating Scales, as well as social functioning and service utilisation. The main analyses will be by intention-to-treat using mixed-model repeated measures with non-parametric methods employed if required. The model of change underpinning ACT will be tested using mediation analyses. DISCUSSION: This protocol describes the first randomised controlled trial of Acceptance and commitment therapy in chronic medication-resistant psychosis with an active comparison condition. The rigor of the design will provide an important test of its action and efficacy in this population. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12608000210370. Date registered: 18 April 2008.

A preliminary investigation on the efficacy of N-acetyl cysteine for mania or hypomania.

OBJECTIVE: Oxidative imbalance has emerged as a treatment target in bipolar disorder. As very limited data are available on the clinical use of antioxidants for mania, we report here results from a post hoc and exploratory subgroup analysis of a randomized, placebo-controlled trial of N-acetyl cysteine (NAC). METHODS: This was a placebo-controlled, randomized, clinical trial assessing the effect of NAC over 24 weeks in mania or hypomania. Symptomatic and functional outcomes were collected over the study period. RESULTS: Fifteen participants were available for this report; two participants in each group failed to complete all assessments. Within-group analyses pointed to an improvement in the NAC group on manic symptoms and worsening in the placebo group on depressive symptoms at endpoint. CONCLUSIONS: Although the sample size was small, these results indicated within-group efficacy for this glutathione precursor as compared to placebo. Future trials specifically designed to demonstrate the efficacy of NAC in mania are needed.

Pharmacological approaches to the management of schizophrenia: 10 years on.

OBJECTIVE: To review the contemporary landscape regarding pharmacological treatments for schizophrenia. METHOD: Selective literature review. RESULTS: Newer antipsychotic agents include aripiprazole, asenapine, paliperidone, sertindole and ziprasidone. Each has some particular benefits and some shortcomings. Overall treatment efficacy (for positive symptoms at least) has not advanced substantially but some newer agents might have a better profile than older typical agents for negative and cognitive symptoms. Metabolic side effects and hyperprolactinaemia remain a problem with some of the newer agents and appropriate monitoring is required. CONCLUSIONS: Whilst newer antipsychotics have been welcome additions to our pharmacological armamentarium, mostly in terms of tolerability, we have still not seen a 'quantum leap' agent brought to market. Mechanisms of action apart from post-synaptic dopamine blockade appear worthy of further investigation in this regard.